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Pyronaridine-artesunate With Low Dose Primaquine for Preventing P. Falciparum Transmission (NECTAR1)

Primary Purpose

Malaria,Falciparum

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Pyronaridine Tetraphosphate/Artesunate
Dihydroartemisinin/Piperaquine
Primaquine Diphosphate
Sponsored by
London School of Hygiene and Tropical Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malaria,Falciparum focused on measuring Primaquine, Pyramax, Euartesim, Dihydroartemisinin-piperaquine, Pyronaridine-artesunate

Eligibility Criteria

5 Years - 50 Years (Child, Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Age ≥ 5 years and ≤ 50 years
  • Absence of symptomatic falciparum malaria, defined by fever on enrolment
  • Presence of ≥16 gametocytes/µL (i.e. ≥1 gametocytes recorded in the thick film against 500 white blood cells)
  • No allergies to study drugs
  • Use of antimalarial drugs over the past 7 days (as reported by the participant)
  • Hemoglobin ≥ 9.5 g/dL
  • Individuals weighing >< 80 kg
  • No evidence of severe or chronic disease
  • Written, informed consent

Exclusion Criteria:

  • Age < 5 years or > 50 years
  • Pregnancy
  • Previous reaction to study drugs/known allergy to study drugs
  • Signs of severe malaria
  • Taking drugs which may be metabolized by cytochrome enzyme CYP2D6 (e.g., flecainide, metoprolol, imipramine, amitriptyline, clomipramine)
  • Blood transfusion within the last 90 days
  • Patients with clinical signs or symptoms of hepatic injury (such as nausea and/or abdominal pain associated with jaundice) or known severe liver disease (i.e. decompensated cirrhosis, Child-Pugh stage B or C).
  • Patients with clinical signs or symptoms of renal impairment or known renal impairment
  • Family history of congenital prolongation of the QTc interval or sudden death or with any other clinical condition known to prolong the QTc interval such as history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease.
  • Taking drugs that are known to influence cardiac function and to prolong QTc interval, such as class IA and III: neuroleptics, antidepressant agents, certain antibiotics including some agents of the following classes - macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, astemizole) and cisapride.
  • Consent not given

Sites / Locations

  • Malaria Research and Training Centre
  • Radboud university medical center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Active Comparator

Active Comparator

Arm Label

Pyronaridine-artesunate (PA)

PA with single low dose primaquine (PQ)

Dihydroartemisinin-piperaquine (DP)

DP with single low dose primaquine (PQ)

Arm Description

Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days.

Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days, and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg.

Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days.

Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days., and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg.

Outcomes

Primary Outcome Measures

Change in mosquito infectivity assessed through membrane feeding assays (day 2)
The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 2 post feed, compared to baseline

Secondary Outcome Measures

Change in mosquito infectivity assessed through membrane feeding assays (day 7)
The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 7 post feed, compared to baseline
Mosquito infectivity assessed through membrane feeding assays - inter arm
Mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 2 and 7 post feed, compared between study arms
Duration of infectivity
Non PQ arms only: Duration of infectivity will be determined from measures of mosquito infection prevalence, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 0, 2, 7, 10 and 14 post treatment, and then weekly until 2 sequential negative feeds or until day 49.
Area under the curve (AUC) of infectivity/time
Non PQ arms only: AUC will be determined from measures of mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 0, 2, 7, 10 and 14 post treatment, and then weekly until 2 sequential negative feeds or until day 49.
Haemoglobin level
Haemolysis will be monitored by measuring haemoglobin levels (g/dL) on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Histidine rich protein 2 (HRP2) concentration
Histidine rich protein 2 (HRP2) protein concentration in plasma will be determined in subsequent lab analysis from samples collected on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Histidine rich protein 2 (HRP2) circulation time
Histidine rich protein 2 (HRP2) protein circulation time will be compared between methods of detection
Histidine rich protein 2 (HRP2) area under the curve (AUC)
Histidine rich protein 2 (HRP2) area under the curve (AUC) will be determined from measures of HRP2 concentration
Rapid diagnostic test result
Varied rapid diagnostic tests based on the detection of HRP2 will be used on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment to determine infection prevalence, for comparison between study arms.
Gametocyte density
Gametocyte density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Gametocyte under the curve (AUC)
Gametocyte area under the curve (AUC) will be determined from measures of density.
Gametocyte prevalence
Gametocyte prevalence (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Gametocyte circulation time
Gametocyte circulation time (days) will be determined from measures of prevalence.
Gametocyte sex ratio
Gametocyte density will be determined by molecular methods for males and females separately, allowing analysis of sex ratio (proportion of total that is male) on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Asexual parasite density
Asexual parasite density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Asexual parasite area under the curve (AUC)
Asexual parasite area under the curve (AUC) will be determined from measures of density.
Asexual parasite prevalence
Asexual parasite prevalence (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Asexual parasite circulation time
Asexual parasite circulation time (days) will be determined from measures of prevalence.
Parasite genotype
Parasite merozoite surface protein 2 (MSP2) allelic diversity (presence of distinct alleles) will be determined in subsequent lab analysis from whole blood samples collected at baseline.
Histidine rich protein gene deletion
Deletion (presence/absence) of the HRP2/3 genes will be determined from whole blood samples collected at baseline.

Full Information

First Posted
July 12, 2019
Last Updated
January 29, 2020
Sponsor
London School of Hygiene and Tropical Medicine
Collaborators
Malaria Research and Training Center, Bamako, Mali, Radboud University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04049916
Brief Title
Pyronaridine-artesunate With Low Dose Primaquine for Preventing P. Falciparum Transmission
Acronym
NECTAR1
Official Title
The Efficacy and Safety of Pyronaridine-artesunate Combined With Low Dose Primaquine for Preventing Transmission of P. Falciparum Gametocytes in Sub-Saharan Africa
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
September 12, 2019 (Actual)
Primary Completion Date
January 7, 2020 (Actual)
Study Completion Date
January 7, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
London School of Hygiene and Tropical Medicine
Collaborators
Malaria Research and Training Center, Bamako, Mali, Radboud University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to assess the gametocytocidal and transmission reducing activity of pyronaridine-artesunate (PA) and dihydroartemisinin-piperaquine (DP) with and without a single low dose of primaquine (PQ; 0.25mg/kg). Outcome measures will include infectivity at 2 and 7 days after treatment, the duration of infectivity in the artemisinin combination therapy (ACT) only arms, and the production and detectability of histidine rich protein II.
Detailed Description
Protocol will be shared on request

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malaria,Falciparum
Keywords
Primaquine, Pyramax, Euartesim, Dihydroartemisinin-piperaquine, Pyronaridine-artesunate

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Masking Description
This is a single blind randomised controlled trial. The treating physician and staff involved with assessing all laboratory outcomes of the study are blinded, but no placebo will be used. The study pharmacist will be unblinded and responsible for randomisation and treatment administration.
Allocation
Randomized
Enrollment
100 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Pyronaridine-artesunate (PA)
Arm Type
Active Comparator
Arm Description
Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days.
Arm Title
PA with single low dose primaquine (PQ)
Arm Type
Experimental
Arm Description
Subjects will receive pyronaridine-artesunate (PA) once daily for 3 days, and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg.
Arm Title
Dihydroartemisinin-piperaquine (DP)
Arm Type
Active Comparator
Arm Description
Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days.
Arm Title
DP with single low dose primaquine (PQ)
Arm Type
Active Comparator
Arm Description
Subjects will receive dihydroartemisinin-piperaquine (DP) once daily for 3 days., and a low dose of primaquine (PQ) on the first dat of treatment. PQ dose is at the World Health Organization (WHO) recommended dose of 0.25 mg/kg.
Intervention Type
Drug
Intervention Name(s)
Pyronaridine Tetraphosphate/Artesunate
Other Intervention Name(s)
Pyramax
Intervention Description
Adults: Tablets containing 180 mg pyronaridine-tetraphosphate/60mg artesunate (Pyramax, Shin Poong Pharmaceutical Co.), administered according to weight. Children: Granules containing 60 mg pyronaridine-tetraphosphate/20mg artesunate, administered according to weight.
Intervention Type
Drug
Intervention Name(s)
Dihydroartemisinin/Piperaquine
Other Intervention Name(s)
Euartesim
Intervention Description
Tablets containing 40 mg dihydroartemisinin/320 mg piperaquine tablets (Eurartesim, Sigma Tau), administered according to weight.
Intervention Type
Drug
Intervention Name(s)
Primaquine Diphosphate
Other Intervention Name(s)
Primaquine
Intervention Description
Extemporaneous preparation of 1mg/mL primaquine phosphate solution, from tablets containing 30mg primaquine (A-PQ 30®, ACE pharmaceuticals, NL) dissolved in 30mL water with a non-interacting fruit-flavoured syrup. Solution will be given at 0.25mg/kg.
Primary Outcome Measure Information:
Title
Change in mosquito infectivity assessed through membrane feeding assays (day 2)
Description
The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 2 post feed, compared to baseline
Time Frame
2 days (day 0 & 2)
Secondary Outcome Measure Information:
Title
Change in mosquito infectivity assessed through membrane feeding assays (day 7)
Description
The proportion of mosquitoes infected, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 7 post feed, compared to baseline
Time Frame
2 days (day 0 & 7)
Title
Mosquito infectivity assessed through membrane feeding assays - inter arm
Description
Mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 2 and 7 post feed, compared between study arms
Time Frame
3 days (day 0, 2 & 7)
Title
Duration of infectivity
Description
Non PQ arms only: Duration of infectivity will be determined from measures of mosquito infection prevalence, assessed through membrane feeding and measured as oocyst prevalence in mosquitoes dissected on day 0, 2, 7, 10 and 14 post treatment, and then weekly until 2 sequential negative feeds or until day 49.
Time Frame
5-10 days (as described)
Title
Area under the curve (AUC) of infectivity/time
Description
Non PQ arms only: AUC will be determined from measures of mosquito infection prevalence and density, assessed through membrane feeding and measured as oocyst prevalence/density in mosquitoes dissected on day 0, 2, 7, 10 and 14 post treatment, and then weekly until 2 sequential negative feeds or until day 49.
Time Frame
5-10 days (as described)
Title
Haemoglobin level
Description
Haemolysis will be monitored by measuring haemoglobin levels (g/dL) on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Time Frame
11 days
Title
Histidine rich protein 2 (HRP2) concentration
Description
Histidine rich protein 2 (HRP2) protein concentration in plasma will be determined in subsequent lab analysis from samples collected on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Time Frame
11 days
Title
Histidine rich protein 2 (HRP2) circulation time
Description
Histidine rich protein 2 (HRP2) protein circulation time will be compared between methods of detection
Time Frame
11 days
Title
Histidine rich protein 2 (HRP2) area under the curve (AUC)
Description
Histidine rich protein 2 (HRP2) area under the curve (AUC) will be determined from measures of HRP2 concentration
Time Frame
11 days
Title
Rapid diagnostic test result
Description
Varied rapid diagnostic tests based on the detection of HRP2 will be used on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment to determine infection prevalence, for comparison between study arms.
Time Frame
11 days
Title
Gametocyte density
Description
Gametocyte density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Time Frame
11 days
Title
Gametocyte under the curve (AUC)
Description
Gametocyte area under the curve (AUC) will be determined from measures of density.
Time Frame
11 days
Title
Gametocyte prevalence
Description
Gametocyte prevalence (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Time Frame
11 days
Title
Gametocyte circulation time
Description
Gametocyte circulation time (days) will be determined from measures of prevalence.
Time Frame
11 days
Title
Gametocyte sex ratio
Description
Gametocyte density will be determined by molecular methods for males and females separately, allowing analysis of sex ratio (proportion of total that is male) on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Time Frame
11 days
Title
Asexual parasite density
Description
Asexual parasite density (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Time Frame
11 days
Title
Asexual parasite area under the curve (AUC)
Description
Asexual parasite area under the curve (AUC) will be determined from measures of density.
Time Frame
11 days
Title
Asexual parasite prevalence
Description
Asexual parasite prevalence (parasites/microlitre) will be measured by microscopy and by molecular methods on days 0, 1, 2, 7, 10, 14, 21, 38, 35, 42 and 49 post treatment.
Time Frame
11 days
Title
Asexual parasite circulation time
Description
Asexual parasite circulation time (days) will be determined from measures of prevalence.
Time Frame
11 days
Title
Parasite genotype
Description
Parasite merozoite surface protein 2 (MSP2) allelic diversity (presence of distinct alleles) will be determined in subsequent lab analysis from whole blood samples collected at baseline.
Time Frame
1 day
Title
Histidine rich protein gene deletion
Description
Deletion (presence/absence) of the HRP2/3 genes will be determined from whole blood samples collected at baseline.
Time Frame
1 day

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Age ≥ 5 years and ≤ 50 years Absence of symptomatic falciparum malaria, defined by fever on enrolment Presence of ≥16 gametocytes/µL (i.e. ≥1 gametocytes recorded in the thick film against 500 white blood cells) No allergies to study drugs Use of antimalarial drugs over the past 7 days (as reported by the participant) Hemoglobin ≥ 9.5 g/dL Individuals weighing >< 80 kg No evidence of severe or chronic disease Written, informed consent Exclusion Criteria: Age < 5 years or > 50 years Pregnancy Previous reaction to study drugs/known allergy to study drugs Signs of severe malaria Taking drugs which may be metabolized by cytochrome enzyme CYP2D6 (e.g., flecainide, metoprolol, imipramine, amitriptyline, clomipramine) Blood transfusion within the last 90 days Patients with clinical signs or symptoms of hepatic injury (such as nausea and/or abdominal pain associated with jaundice) or known severe liver disease (i.e. decompensated cirrhosis, Child-Pugh stage B or C). Patients with clinical signs or symptoms of renal impairment or known renal impairment Family history of congenital prolongation of the QTc interval or sudden death or with any other clinical condition known to prolong the QTc interval such as history of symptomatic cardiac arrhythmias, with clinically relevant bradycardia or with severe cardiac disease. Taking drugs that are known to influence cardiac function and to prolong QTc interval, such as class IA and III: neuroleptics, antidepressant agents, certain antibiotics including some agents of the following classes - macrolides, fluoroquinolones, imidazole, and triazole antifungal agents, certain non-sedating antihistaminics (terfenadine, astemizole) and cisapride. Consent not given
Facility Information:
Facility Name
Malaria Research and Training Centre
City
Bamako
Country
Mali
Facility Name
Radboud university medical center
City
Nijmegen
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Anonymised individual participant data may be shared on a digital repository or upon reasonable request
Citations:
PubMed Identifier
35028628
Citation
Stone W, Mahamar A, Sanogo K, Sinaba Y, Niambele SM, Sacko A, Keita S, Youssouf A, Diallo M, Soumare HM, Kaur H, Lanke K, Ter Heine R, Bradley J, Issiaka D, Diawara H, Traore SF, Bousema T, Drakeley C, Dicko A. Pyronaridine-artesunate or dihydroartemisinin-piperaquine combined with single low-dose primaquine to prevent Plasmodium falciparum malaria transmission in Ouelessebougou, Mali: a four-arm, single-blind, phase 2/3, randomised trial. Lancet Microbe. 2022 Jan;3(1):e41-e51. doi: 10.1016/S2666-5247(21)00192-0.
Results Reference
derived

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Pyronaridine-artesunate With Low Dose Primaquine for Preventing P. Falciparum Transmission

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